In the pharmaceutical and agricultural fields among others, it is often desirable to maintain the concentration of an active agent at a predetermined site for an extended period of time.
For example, in order to maintain a desired concentration of a pharmaceutical composition within a human or animal patient, i.e. within the bloodstream, with a composition administered orally in tablet form, the tablets must be administered regularly. This requirement stems from the fact that, typically, the pharmaceutical composition contained within a tablet is released at once, when the tablet is dissolved in the recipients stomach. Any interruption in the supply of tablets causes a consequent reduction in the concentration of pharmaceutical composition in the blood.
A controlled release tablet releases a pharmaceutical composition in a controlled fashion such that a pharmaceutical composition is released into a patient's stomach at a constant rate for many hours. The rate may be set so as to maintain the desired concentration of pharmaceutical composition in the patient and, the tablet may contain a sufficient amount of said composition to maintain the desired concentration for twelve or more hours. Thus, there is no need for a patient to take tablets both regularly and frequently and the probability of an interruption in a patient's regime is reduced.
Many different devices have been developed to accomplish this result. One such device provides a controlled release via a core tablet including an active agent coated with a semipermeable membrane which has a microscopic passageway therein.
Representative of such a system is U.S. Pat. No. 3,845,770 (Theeuwes et al.). The semipermeable membrane is permeable only to a fluid present in the environment of use (i.e., water), and either the active agent or another component (e.g., sodium chloride) of the core tablet exhibits osmotic activity. Water permeates through the semipermeable membrane due to the presence of the osmotic agent in the tablet core and solubilizes the core. The osmotic pressure differential brings about the release of the active agent through the passageway. The rate of release is said to be dependent upon the permeability of the semipermeable membrane and the osmotic pressure gradient across the semipermeable membrane.
U.S. Pat. No. 4,624,847 (Ayer et al.) describes an osmotic dispensing device wherein a drug is in a compartment surrounded by a semipermeable wall with an osmotic passageway to the compartment. The drug is mixed with an osmopolymer or a with an osmopolymer and an osmagent. The osmopolymer is, for instance a swellable hydrogel which exhibits an osmotic pressure gradient across the semipermeable wall against an external fluid in an environment of use and it imbibes external fluid through the semipermeable wall into the compartment. The osmagent is a salt such as sodium chloride. The osmagent is soluble in the external fluid and, for example, also exhibits an osmotic pressure gradient across the semipermeable wall against the external fluid.
Other patents describing various osmotic dispensing devices having a semipermeable membrane and a passageway through the semipermeable membrane include U.S. Pat. No. 4,519,801 (Edgren); U.S. Pat. No. 4,111,203 (Theeuwes); U.S. Pat. No. 4,777,049 (Magruder et al.); U.S. Pat. No. 4,612,008 (Wong et al.); U.S. Pat. No. 4,610,686 (Ayer et al.); U.S. Pat. No. 4,036,227 (Zaffaroni et al.); U.S. Pat. No. 4,553,973 (Edgren); U.S. Pat. No. 4,077,407 (Theeuwes et al.); and U.S. Pat. No. 4,609,374 (Ayer).
U.S. Pat. No. 4,218,433 (Kooichi et al.) describes another tablet which is said to release active component at a constant rate. A tablet containing a water-soluble component and having a coating which is insoluble in water but has water permeability is formed with an indentation in its surface. When exposed to water, a very small space is said to form between the coating and the indentation, and the coating becomes porous and allows the active component to elute out.
Other devices, such as that described in U.S. Pat. No. 4,687,660 (Baker et al.) provide an osmotic dispensing device which does not use a preformed single passageway to release water-soluble drugs. The device includes a core where drug is combined with excipient and an osmotic enhancing agent. The core is film coated with a solution of a water insoluble, water permeable polymer, a water-permeability enhancing agent such as a polyhydric alcohol, and a water-soluble, polymer-solvent-insoluble, particulate pore-forming material such as lactose. In use, the lactose is leached out as water is imbibed through the film coating. The water dissolves the drug and the osmotic enhancing agent, thereby creating an osmotic gradient.
U.S. Pat. No. 4,816,262 (McMullen) relates to a controlled release tablet having a disc-like configuration with a cylindrical hole extending centrally therethrough which is said to allow for zero order or constant release. The core is a compressed mixture of an active agent and a hydrophilic releasing agent is defined by centrally tapering upper and lower annular faces and outer and inner cylindrical faces. The core is covered with a hydrophobic coating which extends over the upper and lower faces as well as the outer face. Release of the active agent is affected only through a "hole" which comprises the inner cylindrical face.
U.S. Pat. No. 4,814,183 (Zentner) relates to a controlled release device having a core containing a charged resin and a diffusible water soluble ionizable drug having the same charge as the resin. The core is surrounded by a water insoluble wall formed of semi-permeable material which is substantially impermeable to core components and permeable to the passage of an external fluid in the environment of use. The wall has one or more holes for release of the drug. The external fluid actuates the migration of drug away from the charged resin and through the hole.
Other devices have been designed with an impermeable coating covering various portions of the device. For example, U.S. Pat. No. 4,814,182 (Graham et al.) relates to a controlled release device comprising an active ingredient/ hydrogel mixture with at least one surface of the device having a coating which is impermeable to aqueous media. U.S. Pat. No. 4,792,448 (Ranade) relates to a cylindrical tablet or bolus having an active ingredient blended with inert excipients and formed into a cylindrical tablet preferably having a flat cylindrical side and a convex top and bottom. The core is covered with an impermeable coating from which strips of the coating have been removed. U.S. Pat. No. 4,803,076 (Ranade) relates to a controlled release device having an active agent contained within a substantially impermeable coating on the base and side but not the top of a truncated cone.
In "Zero-Order Controlled-Release Polymer Matrices for Micro-and Macromolecules", D. Hsieh et al., J. Pharm. Sciences, Vol. 72, No. 1 (January 1983), a hemispherical polymer-drug matrix laminated with an impermeable coating except for an exposed cavity in the center face is described. The hemispherical devices are made by fusing polyethylene and drug by heating, or by gelation of an ethylene-vinyl acetate copolymer by freezing. The copolymers are then molded into hemispheric pellets with a steel bead press-fitted into a central depression. The pellets were then coated with paraffin or 20% ethylene-vinyl acetate copolymer and the bead removed.